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Transmitted AZT/d4T-Resistant Virus Persists Up 4 Years Without Treatment
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6th European HIV Drug Resistance Workshop
March 26-28, 2008
Budapest, Hungary
Mark Mascolini
HIV potentially resistant to AZT or d4T was the most commonly transmitted virus in the prospective German seroconverter cohort, and it endured in untreated people up to 46 months after they became infected [1].
Researchers at Berlin's Robert Koch Institute genotyped plasma virus from people with a documented date of HIV infection between 1996 and 2007. No one took antiretrovirals during follow-up. Of the 1174 people tested, 148 (12.6%) had a primary antiretroviral resistance mutation, according to the 2007 IAS-USA list [2]. The most frequent mutations, found in 51 people (4.3%), were so-called revertants at reverse transcriptase position 215. T215 revertants are viruses evolving back toward a nonresistant "wild-type" genotype (T215T) from a fully resistant T215Y or T215F genotype. Forty-eight of the 51 people with revertant virus picked up HIV during sex between men, a proportion reflecting the makeup of this seroconverter cohort.
The Koch Institute team spotted nucleoside-resistant HIV in 5.8% of samples tested, nonnucleoside-resistant virus in 2.8%, and protease inhibitor-resistant virus in 2.1%. Only 1.7% of the viruses genotyped had two or more resistance mutations.
Analyzing viral isolates from 17 people with a T215 revertant and follow-up resistance tests, the investigators logged an average 16.6 months of follow-up (interquartile range 12 to 34), from a minimum of 8 months to a maximum of 46. Ten of these 17 people (59%) had one or two other AZT or d4T mutations, but they had no mutations making virus resistant to nonnucleosides or to protease inhibitors.
Twelve of the 17 T215 revertants persisted for an average 14.5 months (interquartile range 11 to 32 months). Of the other five revertants, two evolved to another revertant strain and three evolved back to wild-type 12, 17, and 32 months after these people got infected. The longest-lasting revertant remained detectable for 46 months without antiretroviral therapy. Scrutiny of viral clones created from T215 revertant virus from 5 people confirmed that these potentially resistant strains persisted for at least 1 year and up to 21 months.
The Koch Institute scientists do not believe the 17 people with revertant virus and follow-up genotyping got infected with wild-type virus that somehow evolved into an apparently revertant strain because none of the 17 had wild-type T215 virus in their first sample. And clonal analysis found wild-type virus in only 1 of 10 clones from 1 person infected for 12 months.
Koch investigators found genetic links delineating 10 HIV transmission clusters among the 51 people with revertant virus. Some transmissions occurred more than a year after the source partner got infected with HIV, a finding confirming that persistence of T215 revertants poses a threat to uninfected people.
The researchers proposed that "the pronounced potential of T215-revertants to persist and to spread will impact future treatment options of patients newly infected with T215 revertants." But since almost no one in high-income countries gets d4T in a first regimen--and fewer and fewer get AZT--these findings are not as ominous as they would have seemed a decade ago.
An earlier 405-person cohort study by Italian investigators found a tripled risk of virologic failure in people with a T215 revertant when they began their first regimen containing AZT or d4T [3]. Sixteen people (4%) in this ICoNA cohort had revertant virus when they began treatment.
1. Kuecherer C, Schuenadel L, S. Somogyi S, et al. Transmission and persistence of HIV-1 with thymidine analogue resistance mutations in HIV-1 infected patients with documented date of infection. 6th European HIV Drug Resistance Workshop. March 26-28, 2008. Budapest. Abstract 1.
2. Johnson VA, Brun-Vezinet F, Clotet B, et al. Update of the drug resistance mutations in HIV-1: 2007. Topics HIV Med. 2007;15:119-125.
3. Violin M, Cozzi-Lepri A, Velleca R, et al. Risk of failure in patients with 215 HIV-1 revertants starting their first thymidine analog-containing highly active antiretroviral therapy. AIDS. 2004;18:227-235.
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